Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), affect millions of people. No affective treatments exist, and the molecular mechanisms of neurogeneration are still poorly understood. The cytokine transforming growth factor-beta1 (TGF-beta1) has been implicated in the pathogenesis of AD, PD and stroke. In the central nervous system (CNS), it is rapidly induced in response to injury and has been shown to be neuroprotective in vitro and in vivo. Activation of the TGF-beta signaling pathway in neurons could be a mechanism by which TGF-beta1 protections neurons from degeneration. TGF-beta1 binds to serine-threonine kinase receptors expressed on most cell types, resulting in the phosphorylation of intracellular signaling molecules called Smad proteins. Activated Smads can translocate into the nucleus where they bind to DNA elements and activate the transcription of specific genes. Specific Aim 1: To characterize the TGF-beta signaling and receptor trafficking pathway in Neuro-2a neuroblastoma cells and in primary cortical neurons. The distribution of TGF-beta type I (TBR1) and II (TBR2) receptors and the activation of Smad proteins will be examined in neurons in the presence and absence of recombinant TGF-beta1. Specific Aim 2: To characterize the activation of the TGF-beta signaling pathway in CNS neurons in vivo. The activation of TGF-beta receptors and Smad proteins in neurons in response to kainic acid-induced injury will be examined in normal and mutant mice expressing a signaling-deficient TBR2. Specific Aim 3: To determine whether the absence of TGF-beta signaling in neurons increases their susceptibility to age-related or excitotoxin-induced degeneration.